Liposomal amphotericin B for fever and neutropenia.
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Amphotericin B↗
Biomedical subjects
T Fischer
Publications and source records attributed to T Fischer.
Clathrin-coated vesicles bearing GAIP possess GTPase-activating protein activity in vitro.
Galpha-interacting protein (GAIP) is a member of the RGS (regulators of G protein signaling) family, which serve as GAPs (GTPase-activating proteins) for Galpha subunits. Previously, we demonstrated that GAIP is localized on clathrin-coated vesicles (CCVs). Here, we tested whether GAIP-enriched vesicles could accelerate the GTPase activity of Galphai proteins. A rat liver fraction containing vesicular carriers (CV2) was enriched (4.5x) for GAIP by quantitative immunoblotting, and GAIP was detected on some of the vesicles in the CV2 fraction by immunoelectron microscopy. When liver fractions were added to recombinant Galphai3 and tested for GAP activity, only the CV2 fraction contained GAP activity. Increasing amounts of CV2 increased the activity, whereas immunodepletion of the CV2 fraction with an antibody against the C terminus of GAIP decreased GAP activity. CCV fractions were prepared from rat liver by using a protocol that maintains the clathrin coats. GAIP was enriched in these fractions and was detected on CCVs by immunogold labeling. Addition of increasing amounts of CCV to recombinant Galphai3 protein increased the GTPase activity. We conclude that CCVs possess GAP activity for Galphai3 and that membrane-associated GAIP is capable of interacting with Galphai3. The reconstitution of the interaction between a heterotrimeric G protein and GAIP on CCVs provides biochemical evidence for a model whereby the G protein and its GAP are compartmentalized on different membranes and come into contact at the time of vesicle fusion. Alternatively, they may be located on the same membrane and segregate at the time of vesicle budding.
Animals↗
Regulators of G protein signaling proteins as determinants of the rate of desensitization of presynaptic calcium channels.
Norepinephrine inhibits omega-conotoxin GVIA-sensitive presynaptic Ca2+ channels in chick dorsal root ganglion neurons through two pathways, one mediated by Go and the other by Gi. These pathways desensitize at different rates. We have found that recombinant Galpha interacting protein (GAIP) and regulators of G protein signaling (RGS)4 selectively accelerate the rate of desensitization of Go- and Gi-mediated pathways, respectively. Blockade of endogenous RGS proteins using antibodies raised against Galpha interacting protein and RGS4 slows the rate of desensitization of these pathways in a selective manner. These results demonstrate that different RGS proteins may interact with Gi and Go selectively, giving rise to distinct time courses of transmitter-mediated effects.
Amino Acid Sequence↗
Clinical improvement of HIV-associated psoriasis parallels a reduction of HIV viral load induced by effective antiretroviral therapy.
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Adult↗
[Melatonin in dermatology. Experimental and clinical aspects].
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone with multiple functions in humans, produced by the pineal gland and stimulated by beta-adrenergic receptors. Serum melatonin levels exhibit a circadian rhythm with low levels during the day, rise in the evening and maximum levels at night between 2 and 4 a.m. Melatonin participates in the regulation of several physiological processes such as seasonal biological rhythm, daily sleep induction, aging and modulation of immunobiological defence reactions. Furthermore, melatonin has a highly lipophilic molecular structure facilitating penetration of cell membranes and serving as an extra- and intracellular free radical scavenger. Melatonin seems to quench mainly hydroxyl radicals, the most damaging of all free radicals. Melatonin may play a role in the etiology and treatment of several dermatoses e.g. atopic eczema, psoriasis and malignant melanoma. The influence of melatonin on hair growth is another aspect. Topical application of melatonin inhibits the development of UV-erythema. Penetration through skin after topical application and oral bioavailability auxit further investigations on the pharmacokinetic and pharmacodynamic actions of melatonin.
Animals↗
The DNA-binding subunit p140 of replication factor C is upregulated in cycling cells and associates with G1 phase cell cycle regulatory proteins.
The DNA-binding subunit of replication factor C (RFCp140) plays an important role in both DNA replication and DNA repair. The mechanisms regulating activation of RFCp140 thereby controlling replication and cellular proliferation are largely unknown. We analyzed protein expression of RFCp140 during cell cycle progression and investigated the association of RFCp140 with cell cycle regulatory proteins in cell lines of various tissue origin and in primary hematopoietic cells. Western and Northern blot analyses of RFCp140 from synchronized cells showed downregulation of RFCp140 when cells enter a G0-like quiescent state and upregulation of RFCp140 in cycling cells. Translocation from the cytoplasmic compartment to the nucleus did not account for the significant increase in RFCp140 protein levels observed in cycling cells. To investigate a potential association of RFCp140 with cell cycle regulatory proteins coimmunoprecipitation assays were performed. These studies demonstrated specific binding of RFCp140 to cdk4-kinase in hematopoietic and fibroblast cell lines. Additional coimmunoprecipitation studies revealed specific association of RFCp140 with cyclin D1, p21, proliferating cell nuclear antigen, and retinoblastoma protein. These findings link DNA replication and repair factor RFCp140 to G1 phase cell cycle regulatory elements critically involved in cell cycle control.
3T3 Cells↗
Continuous monitoring of cardiac output in neonates using an intra-aortic Doppler probe.
Continuous monitoring of cardiac output in neonates would be of considerable benefit but, as yet, there is no practical method to achieve this aim. We have now evaluated the feasibility of using an intra-aortic Doppler probe. We introduced a pulsed Doppler probe of 0.46 mm diameter via the umbilical artery in two term and four preterm neonates. Indications in all patients for umbilical arterial catheter is always an unstable cardiopulmonary state. Body weights were between 770 and 3340 g. Velocities of blood flow in the thoracic aorta were continuously recorded to estimate cardiac output on-line for 12 h. No complications were encountered. It proved possible to derive high-quality Doppler curves. The received Doppler signal was stable but it proved sensitive to pathophysiologic changes in flow. Mean velocity of flow in the descending aorta was 16.4 cm/s (range 13.3-19.0 cm/s). We quantified flow by multiplying the mean velocity of the flow by the cross-sectional area of the descending aorta. Calculated mean flow was 135 ml/kg/min (range 111-179 ml/kg/min). These values are consistent with those measured by transcutaneous Doppler, and it should not be raised by left-to-right ductal shunts. This pilot study proved the feasibility of continuous monitoring of cardiac output. The technique should prove of great value in those infants with unstable circulatory conditions, and can be used even in infants with extremely low birth weights.
Cardiac Output↗
A method for measuring dermal exposure to multifunctional acrylates.
UV-curable acrylates are used increasingly for coating wood surfaces in the furniture industry. One of the active components, tripropylene glycol diacrylate (TPGDA), is known to be both an allergen and irritant to the skin. Methods to measure dermal exposure to skin irritants and allergens, such as acrylates, are insufficient for exposure assessment and there is none for this compound. The aim of this investigation was to develop a skin and surface sampling method, based on tape stripping, and a gas chromatographic method for quantitative analysis for assessing occupational skin exposure to multifunctional acrylates. Twelve adhesives were tested for their efficiency to remove TPGDA and UV-coating from a glass surface, the skin of guinea pigs and human volunteers employing the tape-stripping method in order to find the best performing tape. Variables that affect removal efficiency such as the applied dose and its retention time on the skin, tape adhesion time on the skin, and the number of strippings required to detect the contaminant from the skin were studied. Fixomull tape performed the best during sampling and analysis and had the most consistent removal efficiencies for the studied substances. The average removal efficiency with a single stripping at the 2 microliters TPGDA exposed skin sites was 85% (RSD = 14.1), and for UV-resin exposed sites 63% (RSD = 20.2). The results indicated that this method can be used for measuring dermal exposure to multifunctional acrylates efficiently, accurately, and economically. This method provides a sensitive and powerful tool for the assessment of dermal exposure to multifunctional acrylates both from the skin and from other contaminated surfaces in occupational field settings.
Acrylates↗
Randomised double-blind comparison of simethicone with cisapride in functional dyspepsia.
AIM: To compare the efficacy of simethicone with cisapride in patients with functional (non-ulcer) dyspepsia. METHODS: After standardized diagnostic work-up and at least 6-days wash-out of medication, 177 patients with functional dyspepsia were enrolled; 173 of them (age 19-71 years) were randomized and treated using a double-dummy technique with simethicone (84 mg t.d.s.) or cisapride (10 mg t.d.s.). At baseline and after 2 and 4 weeks, the intensity of the symptoms was scored from 0 (absent) to 3 (severe) using a standardized symptom questionnaire. Efficacy of the treatment was judged by the patients as 'very good', 'good', 'moderate' or 'no effect'. RESULTS: A total of 166 patients completed the trial. After 2 and 4 weeks, 34% and 46% (respectively), of the patients treated with simethicone judged the improvement in symptoms to be excellent compared to 13% and 22% (respectively) of patients treated with cisapride (P < 0.01). After 2 weeks the difference in the improvement in the global symptom score was significantly better (Delta30.7%, P < 0.001) for simethicone than for cisapride, while this difference failed statistical significance after 4 weeks (Delta10.2%, P=0.11). CONCLUSIONS: In patients with functional dyspepsia, simethicone relieves symptoms during the first 2 weeks of treatment significantly better than cisapride.
Cisapride↗
Efficacy and toxicity of IFN-alpha2b combined with cytarabine in chronic myelogenous leukaemia.
Newly diagnosed chronic myelogenous leukaemia (CML) patients (n = 65) were treated with interferon (IFN)-alpha2b (5 x 106 IU/d s.c.) combined with monthly courses of cytarabine (20 mg/d s.c. for 14 d). Median age of patients enrolled was 45 years. The endpoints of the study were clinical efficacy and toxicity. The survival rates at 3 years and 5 years were 77% and 56%, respectively. The rate of complete haematological response was 60%. Evaluation of cytogenetic response was available in 29/65 patients. A complete cytogenetic response was seen in 3/29 patients (10%). W.H.O. toxicity grade 3-4 occurred in only 22/523 evaluable treatment cycles. Since the study protocol required intermittent or definitive discontinuation of cytarabine in case of moderate leucopenia (white blood cells (WBC) <5 x 109/l), combined cytopenia (WBC < 5 x 109/l, platelets <100 x 109/l), and isolated moderate thrombocytopenia (<100 x 109/l), the drug had to be discontinued temporarily or definitively in 200 cycles and the dose of cytarabine had to be reduced in 35 cycles. Thus, only 25% of the planned dose of cytarabine could be administered. At this dosage it would appear that cytarabine had no effect on survival and did not improve remission rates. We conclude that a clinical benefit for the addition of cytarabine to the treatment of CML with IFN might only be achieved by the administration of a higher cumulative dose of cytarabine, suggesting that lower leucocyte counts of 2-4 x 109/l have to be tolerated.
Adolescent↗
The radio-radial external fixator in the treatment of fractures of the distal radius.
The technique of radio-radial monobloc-fixation with the small AO external fixator device has been applied to 17 consecutive Colles' fractures. The fracture types were mainly A3 and C2, according to the AO classification. We found this technique to be easy and quick in application and stable in fixation. Direct, precise and atraumatic reduction can be achieved by using the distal pins as joy-sticks. Furthermore, disimpaction of the fracture to regain length is possible without bone grafting. Normal carpal mobility and load transfer is preserved during fracture healing and the injured hand can be used in daily life with certain restrictions. To prevent pin-track infections, early mobilization of the wrist should be avoided. We recommend this technique in the treatment of comminuted AO-type A3 fractures of the distal radius and in certain type C2 cases.
Adolescent↗
Stinging and rosacea.
A total of 32 rosacea patients (25 with the papulopustular type of rosacea and 7 with the erythematotelangiectatic type) and 32 healthy persons were single-blind tested with a solution of 5% lactic acid and pure water applied to their cheeks. Twenty-four patients and 6 controls reacted positively as "stingers" (p<0.001) in this objective test of sensitive skin. All 7 of the patients with erythematotelangiectatic rosacea, but only 17/25 with the papulopustular type, were stingers (n.s.). The reason why some patients react with subjective symptoms, such as itching, burning, stinging, prickling or tingling, is unclear. The findings in this study are not surprising, but do support the theory that impairment due to different stimuli, most likely because of vascular sensitivity, is a central mechanism in the aetiology of rosacea. The correlation between sensitive vessels and sensitive skin has, however, not yet been determined.
Adult↗
Influence of patch-test application tape on reactions to sodium dodecyl sulfate.
There remains much room for improvement in the accuracy of the patch test procedure. There has been a lack of knowledge regarding the possible relationship between the intensity of test reactions and the quality of the tape used to apply patch tests. Using different brands of tape, patches coated with 2 mg/cm2 sodium dodecyl sulfate (SLS) were applied for 24 h to the backs of 10 volunteers. The tape specimens varied in terms of manufacture, elasticity, adhesive strength, and water permeability. The intensity of patch test reactions, evaluated visually and objectively with both the high resolution laser Doppler perfusion imaging technique (HR-LDPI) and transepidermal water loss measurements (TEWL), varied significantly with the different brands of tape. Observed variations in the intensity of reactions to the patch tests could not be explained by any of the 4 tape parameters investigated. In order to attain optimal test quality in the future, both the tape and patches used in the testing system should be standardized and clearly labelled.
Adhesives↗
Objective non-invasive assessment of patch tests with the laser Doppler perfusion scanning technique.
The laser Doppler perfusion scanning technique is an objective, non-invasive assessment method that may be used to assess patch tests. The purpose of this paper is to focus on its clinical use in individuals with light skin, tested with non-pigmented test materials. A laser Doppler perfusion imager PIM 1.0 (LDPI) is used to study different set-ups of the instrument that may affect readings. These set-ups are studied through simulated light-absorbing patch tests. The results have served as a base for clinical experiments comparing visual and LDPI assessments of normal skin, irritant patch-test reactions, and more than 25,000 allergic patch-test assessments of reactions of different intensities and control patches. This paper reviews the clinical experiments to suggest a set-up of the LDPI for patch-test readings. Such a set-up makes it possible to compare intra- and inter-individual test results and to obtain meaningful assessment values among users. Some subject-related factors that may affect reading results are studied, and the effect of non-subject related factors on readings are considered. Use of the technique is illustrated by images of perfusion and a perfusion profile of a patch-test reaction followed over time.
Anti-Inflammatory Agents↗
Effects of various grit-containing cleansers on skin barrier function.
Products intended for individuals in contact with strongly adhering dirt often contain grit. Various clinical test methods have been developed for evaluating the potential of personal washing products to induce skin irritation. In the present study, differences in the irritant effects of washing products containing naturally-derived grit and synthetic grit were investigated in a forearm wash test. The forearms of 16 test subjects were washed in a total of 18 treatments (4 per day for 4 days, with 2 treatments on the 5th day). Treatment consisted of continuous washing for 2 min by a technician, who gently slid his fingertips with the lather up and down the forearm. Non-invasive instrumental measurements of skin barrier function were performed. Repetitive washing for 1 week lead to increased TEWL values, skin redness and decreased stratum corneum hydration. Results indicate differences in irritancy potential due to different types of grit, their surface and concentration. It is concluded that the repeated wash test seems to be adequate for rating personal washing products that contain grit.
Dermatitis, Contact↗
Assessment of budesonide patch tests.
Patch-test technique for budesonide needs improvement. 20 subjects with positive or questionable patch-test responses to budesonide were retested for 3 to 96 h (4 days [D]) with polyester patches coated with budesonide in serial doses (150 to 0.074 microg/cm2). Multiple readings were taken visually and with a laser Doppler perfusion imaging technique up to 264 h (day [D]11). Additionally, all subjects were tested with 0.1% budesonide in petrolatum in Finn Chambers for 48 h (2D) with readings taken at 72 (D3), 96 (D4) and 168 h (D7). Different dose levels and application times affected unpredictably highest assessments of reactions. No clear suppression of reactivity was observed at high doses. Time points of highest assessments of reactions varied between subjects but were generally the same for each subject with both reading methods regardless of dose levels or application times. Positive and negative subjects during the study were easily distinguished with all serial doses, regardless of assessment technique. At 2.0 microg/cm2, the lowest dose level tested on all subjects, longer applications than 24 h (1D) were required to detect all positive subjects. 48-h (2-D) applications required 2 readings, optimally at 96 (D4) and 216 h (D9). The only test technique with Finn Chambers used here did not make such distinction possible.
Adolescent↗
Reactivity at edges of corticosteroid patch tests may be an indicator of a strong positive test response.
BACKGROUND: The importance of the reactivity at the edges of corticosteroid patch tests is unknown. OBJECTIVE: To study the clinical importance of edge reactivity in budesonide patch tests. METHODS: Ten subjects previously positive for budesonide patch tests were retested with 0.1% budesonide in Finn Chambers((R)) and with budesonide-printed polyester squares in serial doses (150-0.074 microg/cm(2)). Six exposure periods were used for each polyester square dose (3 h to 4 days). Tests were followed up to 11 days. Doubtful or weakly visible reactivity at the test edges was assessed additionally by test perfusion assessments. RESULTS: Nine of 10 subjects reacted with some edge reactivity and later exhibited positive reactions. Perfusion assessments helped to confirm early edge reactivity. Some allergic subjects showed edge reactivity only at high doses, while longer applications were required for weaker doses. CONCLUSION: Edge reactivity may be an indicator of a strong suppressed test response.
Administration, Topical↗
Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor.
Immune mechanisms and the renin-angiotensin system are implicated in preeclampsia. We investigated 25 preeclamptic patients and compared them with 12 normotensive pregnant women and 10 pregnant patients with essential hypertension. Antibodies were detected by the chronotropic responses to AT1 receptor-mediated stimulation of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists. Immunoglobulin from all preeclamptic patients stimulated the AT1 receptor, whereas immunoglobulin from controls had no effect. The increased autoimmune activity decreased after delivery. Affinity-column purification and anti-human IgG and IgM antibody exposure implicated an IgG antibody directed at the AT1 receptor. Peptides corresponding to sites on the AT1 receptor's second extracellular loop abolished the stimulatory effect. Western blotting with purified patient IgG and a commercially obtained AT1 receptor antibody produced bands of identical molecular weight. Furthermore, confocal microscopy of vascular smooth muscle cells showed colocalization of purified patient IgG and AT1 receptor antibody. The protein kinase C (PKC) inhibitor calphostin C prevented the stimulatory effect. Our results suggest that preeclamptic patients develop stimulatory autoantibodies against the second extracellular AT1 receptor loop. The effect appears to be PKC-mediated. These novel autoantibodies may participate in the angiotensin II-induced vascular lesions in these patients.
Amino Acid Sequence↗